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CYP2A6 genetic variation and dexmedetomidine disposition

  • Pharmacogenetics
  • Published:
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Abstract

Purpose

There is a large interindividual variability in dexmedetomidine dose requirements for sedation of patients in intensive care units (ICU). Cytochrome P450 2A6 (CYP2A6) mediates an important route of dexmedetomidine metabolism, and genetic variation in CYP2A6 affects the clearance of other substrate drugs. We examined whether CYP2A6 genotypes affect dexmedetomidine disposition.

Methods

In 43 critically ill ICU patients receiving dexmedetomidine infusions adjusted to achieve the desired level of sedation, we determined a median of five plasma dexmedetomidine concentrations each. Forty subjects were genotyped for five common CYP2A6 alleles and grouped into normal (n = 33), intermediate (n = 5), and slow metabolizers (n = 2).

Results

Using a Bayesian hierarchical nonlinear mixture model, estimated dexmedetomidine clearance was 49.1 L/h (posterior mean; 95% credible interval 41.4–57.6 L/h). There were no significant differences in dexmedetomidine clearance among normal, intermediate, and slow CYP2A6 metabolizer groups.

Conclusion

Genetic variation in CYP2A6 does not appear to be an important determinant of dexmedetomidine clearance in ICU patients.

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Acknowledgments

We would like to thank Dr. Päivi Poijärvi-Virta, Ph.D. (Researcher, Clinical Research Services Turku, University of Turku, Turku, Finland) for the technical performance of the dexmedetomidine assay, and Ewa Hoffmann, M.Sc. (Research Associate, Centre for Addiction and Mental Health and University of Toronto, Toronto, Ontario, Canada) and Qian Zhou, Ph.D. (Research Associate, Centre for Addiction and Mental Health and University of Toronto, Toronto, Ontario, Canada) for their assistance with the genotyping.

Competing interests

Dr. Tyndale is a shareholder and chief scientific officer of Nicogen Inc., a company focused on the development of novel smoking cessation therapies; no funds were received from Nicogen for these studies nor was this manuscript reviewed by other people associated with Nicogen. Dr. Tyndale is a paid advisor to pharmaceutical companies that market or are developing smoking cessation medications.

The laboratory of Dr. Scheinin has contract research relationships with Orion Corporation (Espoo, Finland) and Hospira (Lake Forest, IL, USA). Hospira has a license agreement with Orion Corporation concerning dexmedetomidine (Precedex®). Dr. Scheinin has received speaker fees and consulting fees from Orion Corporation, Dr. Pandharipande has received research funding and honoraria from Hospira Inc., and Dr. Ely has received honoraria and grants from Hospira, Lilly, Pfizer, Glaxo Smith Kline, and Aspect Medical. None of the other authors has a conflict of interest relevant to the work presented.

Funding

This work was supported by Vanderbilt Clinical and Translational Science Award from the National Center for Research Resources [1 UL 1 RR024975]; National Institutes of Health grants [P01 HL56693, R21 AG034412, GM31304, and DA 020830]; and Center for Addiction and Mental Health and the Canadian Institutes for Health Research grant [MOP86471]. Dr. Pandharipande is supported via the Veterans Affairs Career Development Award, the American Society of Critical Care Anaesthesiologists-Foundation for Anaesthesia Education and Research Mentored Research Grant and the Vanderbilt Physician Scientists Development Award. Dr. Ely is supported by a Veterans Affairs Merit Award and National Institutes of Health grant [R01 AG027472-01A1]. Dr. Tyndale is a recipient of a Canada Research Chair in Pharmacogenetics. Dr. Choi is supported by National Institutes of Health grant [R21 AG034412]. Dr. Stein is the recipient of the Dan May Chair in Medicine.

Author information

Authors and Affiliations

  1. Departments of Medicine and Pharmacology, Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA

    Utkarsh Kohli, Mordechai Muszkat, Gbenga G. Sofowora, Eitan A. Friedman, C. Michael Stein & Daniel Kurnik

  2. Division of Critical Care Medicine, Department of Anaesthesiology, Vanderbilt University, Nashville, TN, USA

    Pratik Pandharipande

  3. Department of Pharmacology, Drug Development and Therapeutics, University of Turku, and Clinical Pharmacology, TYKSLAB, Hospital District of Southwest Finland, Turku, Finland

    Mika Scheinin

  4. Weil Cornell Medical School, New York, NY, USA

    Alastair J. J. Wood

  5. Symphony Capital, New York, NY, USA

    Alastair J. J. Wood

  6. Department of Medicine and Health Service Research, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, TN, USA

    E. Wesley Ely

  7. Geriatric Research Education and Clinical Center (GRECC), Veterans Affairs Tennessee Valley Health Care System, Nashville, TN, USA

    E. Wesley Ely

  8. Centre for Addiction and Mental Health and Department of Pharmacology, University of Toronto, Toronto, ON, Canada

    Rachel F. Tyndale

  9. Department of Biostatistics, Vanderbilt University, Nashville, TN, USA

    Leena Choi

  10. Institute of Clinical Pharmacology, Sheba Medical Center, Ramat Gan, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Daniel Kurnik

  11. Division of Clinical Pharmacology, 542 RRB, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA

    Daniel Kurnik

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  1. Utkarsh Kohli
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  7. Alastair J. J. Wood
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  8. E. Wesley Ely
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  9. Rachel F. Tyndale
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  11. C. Michael Stein
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  12. Daniel Kurnik
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Corresponding author

Correspondence to Daniel Kurnik.

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Kohli, U., Pandharipande, P., Muszkat, M. et al. CYP2A6 genetic variation and dexmedetomidine disposition. Eur J Clin Pharmacol 68, 937–942 (2012). https://doi.org/10.1007/s00228-011-1208-z

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  • DOI: https://doi.org/10.1007/s00228-011-1208-z

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